Farnesyl transferase inhibitors

ABSTRACT

A family of tetrahydroimidazo[1,2a]pyrazine based compounds capable of inhibiting the activity of farnesyl transferase and treating tumors and restenosis having the following structure:                  
 
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the specification.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.08/752,546, filed Nov. 20, 1996, which issued as U.S. Pat. No. 6,673,927on Jan. 6, 2004, which claims the benefit of U.S. ProvisionalApplication Ser. No. 60/049,997, filed Feb. 16, 1996.

BACKGROUND OF THE INVENTION

Ras is a 21,000 molecular weight protein important in the signaltransduction pathway for normal cell growth. The protein is produced inthe ribosome, released into the cytosol, and post-translationallymodified. The first step in the series of post-translationalmodifications is the alkylation of Cys¹⁶⁸ with farnesyl pyrophosphate ina reaction catalyzed by the enzyme farnesyl transferase (Hancock, J F,et al., Cell 57:1167–1177 (1989)). Subsequently, the three C-terminalamino acids are cleaved (Gutierrez, L, et al., EMBO J. 8:1093–1098(1989)), and the terminal Cys¹⁶⁸ is methyl esterified (Clark, S, et al.,Proc. Nat'l Acad. Sci. (USA) 85:4643–4647 (1988)). Some forms of Ras arealso reversibly palmitoylated on cysteine residues immediatelyN-terminal to Cys¹⁶⁸ (Buss, J E, et al., Mol. Cell. Biol. 6:116–122(1986)). These modifications increase the hydrophobicity of theC-terminal region of Ras, causing it to localize at the surface of thecell membrane. Localization of Ras to the cell membrane is necessary fornormal function (Willumsen, B M, et al., Science 310:583–586 (1984)).

Oncogenic forms of Ras are observed in a relatively large number ofcancers including over 50 percent of colon cancers, over 30 percent oflung cancers, and over 90 percent of pancreatic cancers (Bos, J L,Cancer Research 49:4682–4689 (1989)). These observations suggest thatintervention in the function of Ras mediated signal transduction may beuseful in the treatment of cancer.

Previously, it has been shown that the C-terminal tetrapeptide of Rashas the “CAAX” motif (wherein C is cysteine, A is an aliphatic aminoacid, and X is any amino acid). Tetrapeptides having this structure havebeen shown to be inhibitors of farnesyl transferase (Reiss, et al., Cell62:81–88 (1990)). Poor potency of these early farnesyl transferaseinhibitors has prompted the search for new inhibitors with morefavorable pharmacokinetic behavior (James, G L, et al., Science260:1937–1942 (1993); Kohl, N E, et al., Proc. Nat'l Acad. Sci. (USA)91:9141–9145 (1994); deSolms, S J, et al., J. Med. Chem. 38:3967–3971(1995); Nagasu, T, et al., Cancer Research 55:5310–5314 (1995); Lerner,E C, et al., J. Biol. Chem. 270:26802–26806 (1995)).

Recently, it has been shown that a farnesyl transferase inhibitor willblock growth of Ras-dependent tumors in nude mice (Kohl, N E, et al.,Proc. Nat'l Acad. Sci. (USA) 91:9141–9145 (1994)). In addition, it hasbeen shown that over 70 percent of a large sampling of tumor cell linesare inhibited by farnesyl transferase inhibitors with selectivity overnon-transformed epithelial cells (Sepp-Lorenzino, I, et al., CancerResearch, 55:5302–5309 (1995)).

SUMMARY OF THE INVENTION

In one aspect, the invention features a compound having the formula (I)or formula (II):

wherein:

R₁ is H, lower alkyl, cycloalkylthio, or lower alkylthio, or, togetherwith R₂, form —CH₂— or —C(CH₃)₂—;

each of R₂ and R₃, independently, is H, lower alkyl, and cycloalkyl;

R₄ is H₂ or O;

R₅ is H, or substituted or unsubstituted lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl,cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, orheterocyclyl lower alkyl, wherein the substituent is lower alkyl,—O—R₁₀, —S(O)_(m)R₁₀ (where m is 0, 1, or 2), —N(R₁₀)(R₁₁), —N—C(O)—R₁₀,—NH—(SO₂)—R₁₀; —CO₂—R₁₀, —C(O)—N(R₁₀)(R₁₁), or —(SO₂)—N(R₁₀)(R₁₁);

each of R₆ and R₇, independently, is H, —C(O)—NHCHR₁₃CO₂R₁₄, orsubstituted or unsubstituted lower alkyl, cycloalkyl, cycloalkyl loweralkyl, cycloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl,heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent isOH, lower alkyl, lower alkoxy, aryloxy, aryl lower alkoxy, —N(R₁₀)(R₁₁),—COOH, —CON(R₁₀)(R₁₁), or halo, or R₆ and R₇, together, form aryl orheterocyclyl;

each of R₈ and R₉, independently, is H, or substituted or unsubstitutedlower alkyl, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl,cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, orheterocyclyl lower alkyl, wherein the substituent is OH, lower alkyl,lower alkoxy, —N(R₁₀)(R₁₁), COOH, —C(O)N—(R₁₀)(R₁₁), or halo, or R₈ andR₉, together, form aryl or heterocyclyl;

each of R₁₀ and R₁₁, independently, is H, lower alkyl, aryl, aryl loweralkyl, cycloalkyl, cycloalkyl lower alkyl, heterocyclyl, or heterocyclyllower alkyl;

R₁₂ is NR₉, S, or O;

R₁₃ is substituted or unsubstituted lower alkyl wherein the substituentis lower alkyl, —OR₁₀, —S(O)_(m)R₁₀ (wherein m is 0, 1, or 2) or—N(R₁₀)(R₁₁); and

R₁₄ is H or lower alkyl; or a pharmaceutically acceptable salt thereof.

Examples of the present invention include the following:

-   7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine    (Compound 1);-   7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(4-fluorophenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine    (Compound 2);-   7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine    (Compound 3);-   7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(3-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine    (Compound 4);-   7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine    (Compound 5);-   7-(2-amino-1-oxo-3-thio-propyl)-8-(2-hydroxy-ethyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine    (Compound 6);-   7-(2-amino-3-thio-propyl)-8-butyl-3-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine    (Compound 7);-   2-(1-(N-(2-amino-1-oxo-3-thiopropyl)-N-methyl)-amino-pentyl)-5-phenyl-imidazole    (Compound 8);-   2-(((2-amino-1-oxo-3-mercapto-propyl)-amino)-methyl)-5-phenyl-thiazole-4-carbonyl-methionine    (Compound 9);-   7-(2-amino-1-oxo-3-thio-propyl)-2-(2-methoxyphenyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine    (Compound 11);-   7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-ethoxyphenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine    (Compound 13);-   7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-hydroxyphenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine    (Compound 14);-   2-(1-(N-(2-amino-1-oxo-3-thiopropyl)-N-methyl)-amino-pentyl-5-(2-methoxyphenyl)-imidazole    (Compound 15);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(2-methylpropyl)-2-(1-naphthyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 17);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 18);-   S-(dimethylethyl)-s′-[2-amino-3-oxo-3(8-butyl-2-(2-methoxyphenyl;)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)propyl]disulfide    (Compound 21);-   7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 22);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(1,1-dimethylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 24);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-(phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 25);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 26);-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydroimidazo[1,2a]]pyrazine    (Compound 27);-   7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2(2-hydroxy-6-methoxyphenyl)-5,6,7,8-tetrahydro[1,2a]pyrazine    (Compound 29);-   2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydro-7-((thiazolidin-4-yl)carbonyl)-imidazo[1,2a]pyrazine    (Compound 31);-   7-(2-amino-1-oxo-3-thiopropyl)-3-bromo-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine    (Compound 32);-   7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2,3-diphenyl-5,6,7,8-tetrahydroimidazo-[1,2a]pyrazine    (Compound 34);-   7-(2-amino-1-oxo-3-thiopropyl)-3-bromo-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine    (Compound 36);-   7-(2-amino-1-oxo-3-thiopropyl)-2-cyclohexyl-8-(cyclohexylmethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine    (Compound 37);-   7-(2-amino-1-oxo-3-thiopropyl)-8-hexyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine    (Compound 42);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 44);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 46);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(2-(4-methoxycyclohexyl)-methyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 47);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 49);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(4-methoxycyclohexyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 51);-   [S-[2-amino-3-oxo-3-(8-cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazin-7-yl)-propyl]-S′-cyclohexyl]disulfide    (Compound 52);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(4-methoxycyclohexyl)    methyl-2-(2-methoxyphenyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine    (cis isomer) (Compound 53);-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(4-piperidinylmethyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine    (Compound 54);-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(2-piperidinylmethyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine    (Compound 55);-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(3-piperidinylmethyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine    (Compound 56);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(1-naphthyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 57);-   [S-[2-amino-3-oxo-3-(8-cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazin-7-yl)-propyl]-S′-ethyl]disulfide    (Compound 58);-   7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(2-methylthio)-ethyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 59);-   7-(2-amino-1-oxo-3-thiopropyl)-8-(3-indolinylmethyl)-2-(2-methoxyphenyl)-8-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 60); and-   7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylimidazol-3-yl)    methyl-2-(2-methoxyphenyl)-8-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    (Compound 61).

In another aspect, the invention features a dimeric compound made of twoidentical or different compounds (monomers) as described above, or apharmaceutically acceptable salt thereof. The monomers are linked toeach other to form the dimer via a disulfide bond. More specifically, R₁in the first monomer and R₁ in the second monomer, in combination, forma disulfide bond.

Examples of dimers of the invention include:

-   bis-1,1′-[2-amino-3-(8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine-7-yl)-3-oxo]propyl    disulfide;-   bis-1,1′-[2-amino-3-(2-(2-methoxyphenyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine-7-yl)-3-oxo]propyl    disulfide;-   bis-1,1′-[2-(1-(N-(2-amino-1-oxo-3-thiopropyl)-N-methylamino)-pentyl]-5-(2-methoxyphenyl)imidazole]disulfide    (Compound 16);-   bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl    -(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)disulfide    (Compound 19).-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide    (Compound 20);-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide    (Compound 23).-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydroimidazo[1,2a]]pyrazine]disulfide    (Compound 28).-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(1,1-dimethylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide    (Compound 30);-   bis-1,1′-[2-amino-3-(8-butyl-2-cyclohexyl-5,6,7,8-tetrahydro-imidazo-[1,2a]pyrazin-7-yl)-3-oxo-propyl]disulfide    (Compound 33);-   bis-1,1′-[2-amino-3-(3-bromo-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]-pyrazin-7-yl)-3-oxo-propyl]disulfide    (Compound 35);-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2,3-diphenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide    (Compound 38);-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-(phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide    (Compound 39);-   bis-1,1′-[2-amino-3-(2-cyclohexyl-8-(cyclohexylmethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazin-7-yl)-3-oxo-propyl]disulfide    (Compound 40);-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide    (Compound 41);-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-hexyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine]disulfide    (Compound 43);-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide    (Compound 45);-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide    (Compound 48); and-   bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(2-(4-methoxycyclohexyl)-methyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide    (Compound 50);

The structures of these compounds are listed in Table I below.

TABLE I COMPOUND 1

COMPOUND 2

COMPOUND 3

COMPOUND 4

COMPOUND 5

COMPOUND 6

COMPOUND 7

COMPOUND 8

COMPOUND 9

COMPOUND 10

COMPOUND 11

COMPOUND 12

COMPOUND 13

COMPOUND 14

COMPOUND 15

COMPOUND 16

COMPOUND 17

COMPOUND 18

COMPOUND 19

COMPOUND 20

COMPOUND 21

COMPOUND 22

COMPOUND 23

COMPOUND 24

COMPOUND 25

COMPOUND 26

COMPOUND 27

COMPOUND 28

COMPOUND 29

COMPOUND 30

COMPOUND 31

COMPOUND 32

COMPOUND 33

COMPOUND 34

COMPOUND 35

COMPOUND 36

COMPOUND 37

COMPOUND 38

COMPOUND 39

COMPOUND 40

COMPOUND 41

COMPOUND 42

COMPOUND 43

COMPOUND 44

COMPOUND 45

COMPOUND 46

COMPOUND 47

COMPOUND 48

COMPOUND 49

COMPOUND 50

COMPOUND 51

COMPOUND 52

COMPOUND 53

COMPOUND 54

COMPOUND 55

COMPOUND 56

COMPOUND 57

COMPOUND 58

COMPOUND 59

COMPOUND 60

COMPOUND 61

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention. For simplicity, where no specific configurationis depicted in the structural formulae, it is understood that allenantiometric forms and mixtures thereof are represented.

As used herein, “lower alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having 1–6 carbonatoms. Examples of lower alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, t-butyl, isobutyl, sec-butyl, and the like. “Loweralkenyl” groups include those groups having 2–6 carbon atoms and havingone or several double bonds. Examples of alkenyl groups include vinyl,allyl, isopropenyl, butenyl, pentenyl, hexenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, isoprenyl, and the like. “Alkynyl groups” includethose groups having 2–6 carbon atoms and having one or several triplebonds. Examples of alkynyl groups include ethynyl, propynyl, 1-butynyl,2-butynyl, 3-butynyl, s-butynyl, and the like. All alkyl, alkenyl, andalkynyl groups are noncyclic.

As used herein, “cycloalkyl” is intended to include non-aromatic cyclichydrocarbon groups having 3–10 carbon atoms. Examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclobenzyl, andthe like. “Cycloalkenyl” is intended to include non-aromatic hydrocarboncyclic groups having 3–10 carbon atoms and having one or several doublebonds. Examples of cycloalkenyl groups include cyclopropenyl,cyclobutenyl, cyclopentenyl, and cyclohexyl, and the like.

As used herein, “aryl” is intended to include phenyl, naphthyl,anthracenyl, biphenyl, tetrahydronaphthyl, indanyl and phenanthrenyl.

The term heterocyclyl, as used herein, is intended to include azepinyl,benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranylsulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide,quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl and thienyl.

The term halo is meant to include fluoro, chloro, bromo, and iodo.

The term “substituted” is meant to include the recited chemical group(e.g., lower alkyl, heterocycle, aryl, cycloalkyl, etc.) substitutedwith one to four of the recited substituents (e.g., halo, OH, loweralkyl, etc.). The substituent may be attached to any atom in thechemical group.

The compounds of this invention can be provided in the form ofpharmaceutically acceptable salts. Acceptable salts include, but are notlimited to, acid addition salts of inorganic acids such ashydrochloride, sulfate, phosphate, diphosphate, hydrobromide, andnitrate or organic acids such as acetate, maleate, fumarate, tartrate,succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate,pamoate, salicylate, oxalate, and stearate. Also within the scope of thepresent invention, where applicable, are salts formed from bases such assodium or potassium hydroxide. For further examples of pharmaceuticallyacceptable salts see, “Pharmaceutical Salts,” J. Pharm. Sci. 66:1(1977).

In another aspect, the invention features a method of inhibitingfarnesyl transferase in a patient, e.g., a mammal such as a human, byadministering to a patient a therapeutically effective amount of acompound of formula (I) or formula (II). In particular, the presentinvention also covers a method of treating restenosis or tissueproliferative diseases (i.e., tumor) in a patient by administering to apatient a therapeutically effective amount of a compound or its salt.Examples of tissue proliferative disease include both those associatedwith benign (e.g., non-malignant) cell proliferation such as fibrosis,benign prostatic hyperplasia, atherosclerosis, and restenosis, and thoseassociated with malignant cell proliferation, such as cancer (e.g.,tumors expressing farnesyl transferase). Examples of treatable tumorsare breast, colon, pancreas, prostate, lung, ovarian, epidermal, andhematopoietic cancers (Sepp-Lorenzino, I, et al., Cancer Research55:5302 (1995)).

A therapeutically effective amount of a compound of this invention and apharmaceutically acceptable carrier substance (e.g., magnesiumcarbonate, lactose, or a phospholipid with which the therapeuticcompound can form a micelle) together form a therapeutic composition(e.g., a pill, tablet, capsule, or liquid) for administration (e.g.,orally, intravenously, transdermally, or subcutaneously) to a subject inneed of the compound. The pill, tablet, or capsule can be coated with asubstance capable of protecting the composition from the gastric acid orintestinal enzymes in the subject's stomach for a period of timesufficient to allow the composition to pass undigested into thesubject's small intestine.

The dose of a compound of the present invention for treating theabove-mentioned diseases or disorders varies depending upon the mannerof administration, the age and the body weight of the subject, and thecondition of the subject to be treated, and ultimately will be decidedby the attending physician or veterinarian. Such an amount of thecompound as determined by the attending physician or veterinarian isreferred to herein as a “therapeutically effective amount.”

Also contemplated within the scope of the invention is a method ofpreparing the compound of formula (I) or formula (II) and the novelchemical intermediates used in these syntheses as described herein.

Other features and advantages of the present invention will be apparentfrom the detailed description of the invention and from the claims.

DESCRIPTION OF THE INVENTION

It is believed that one skilled in the art can, based on the descriptionherein, utilize the present invention to its fullest extent. Thefollowing specific embodiments are to be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Also, all publications, patentapplications, patents, and other references mentioned herein areincorporated by reference.

Synthesis

The following is a description of the synthesis of compounds 1 to 31.Other compounds of the invention can be prepared in an analogous mannerby a person of ordinary skill in the art. As used herein, the term Cbzmeans carbobenzyloxy; DMF means dimethylformamide; EtOAc means ethylacetate, NH₄OAc means ammonium acetate; LAH means lithium aluminumhydride; THF means tetrahydrofuran; BOC means t-Butoxycarbonyl; Trtmeans trityl; Tfa means trifluoroacetic acid; Et₂O means ethyl ether;NMR means nuclear magnetic resonance; mass spec. means massspectroscopy; DMSO-d6 means methyl sulfoxide; DCC means dicyclohexylcarbodiimide; NMM means 4-methyl morpholine; iPr₃SiH meanstriisopropylsilane, HPLC means high performance liquid chromatography;DIC means diisopropylcarbodiimide; MeOH means methanol; KOtBu meanspotassium tert-butoxide; HOSU means N-hydroxysuccinimide; and iBuOCOClmeans isobutyl chloroformate.

EXAMPLE 17-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine(Compound 1)

Compound 1 was synthesized according to synthetic scheme 1 as shownbelow:

a. 2-[1-(S)-(((Phenylmethoxy)carbonyl)amino)-pentyl]-4-phenyl-imidazole

Cbz-(L)-Norleucine (10.0 g, 37.7 mmole) and Cs₂CO₃ (6.14 g, 18.9 mmole)were combined in 1:1/DMF:H₂O (75 ml), and the mixture was swirled untila homogeneous mixture was obtained. Solvents were removed in vacuo. Theresidue was dissolved in DMF (50 ml), and the solvents were removed invacuo again to remove any residual H₂O. The residue was dissolved in DMF(50 ml), and 2-bromoacetophenone (7.5 g, 37.7 mmole) in DMF (25 ml) wasadded to the solution. The solution was stirred for 15 min. at roomtemperature and then concentrated in vacuo. The resulting keto-ester wasdissolved in EtOAc (75 ml), CsBr was filtered off, and the solution wasconcentrated in vacuo. NH₄OAc (50.0 g, 0.65 mole) and xylenes (150 ml)were added to the solution, and the solution was heated at reflux for1.5 hr. The solution was then cooled, and the solvents were removed invacuo. The residue was dissolved in EtOAc (75 ml) and washed two timeswith saturated NaHCO₃ solution (50 ml). The EtOAc layer was then driedover MgSO₄, filtered, and hexanes were added to turbidity. The resultingcrystalline product was filtered off, and the product was dried to yield10.04 g (73%) of product. m.r.=136–138 C, Mass spec. (MH⁺364.3). NMR(300 MHz, CD₃CO₂D) 7.7 (3H, m), 7.4 (3H, m), 7.3 (5H, m), 5.1 (3H, m),2.1 (2H, m (obscured by solvent)), 1.4 (4H, M), 0.9 (3H, t).

b. Ethyl,2-[1-(S)-(((Phenylmethoxy)carbonyl)amino)-pentyl]-4-phenyl-1-imidazoleacetate

Ethyl bromoacetate (2.64 ml, 24 mmole), K₂CO₃ (1.93 g, 14.0 mmole), andintermediate 1a (4.36 g, 12.0 mmole) were mixed in DMF (25 ml), and themixture was heated at 60° C. for 4 hr. The mixture was then concentratedin vacuo and the residue was dissolved in EtOAc (50 ml). The solutionwas washed with both a saturated NaHCO₃ solution (25 ml) and a saturatedNaCl solution (25 ml). The solution was then dried over MgSO₄, filtered,and the solvents were removed in vacuo. The residue was further purifiedby flash chromatography on silica gel using 80:20/hexanes:EtOAc as aneluant. Pure product fractions were combined and concentrated in vacuoto yield an oil which was crystallized. as 3.09 g (57%) of product.m.r.=85–87° C., mass spec. 450.2 (MH+), 472.2 (MNa+). NMR (300 MHz,CD₃CO₂D) 7.7 (2H, d), 7.5 (1H, s), 7.2–7.45 (8H, m), 5.25 (2H, dd), 5.1(2H, dd), 5.1 (1H, m), 2.15 (2H, m), 1.4 (7H, m), 0.9 (3H, t).

c. (S)-8-Butyl-6-oxo-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine

Intermediate 1c (2.89 g, 6.44 mmole) was dissolved in 50 ml acetic acidcontaining 290 mg of 10% Pd on carbon. The mixture was hydrogenated for8 hrs at room temperature. The catalyst was removed by filtrationthrough celite. Lactamization was accomplished by heating at 70° C. for3 hrs. The product was concentrated under reduced pressure, and theresidue was distributed between EtOAc and a saturated NaHCO₃ solution.The EtOAc layer was dried over MgSO₄ and filtered. The product wascrystallized from EtOAc/hexanes to yield 1.37 g (79%) of product.m.r.=208–211 C, mass spec. 270.2 (MH+), 292.2 (MNa+). NMR (300 MHz,CD₃CO₂D) 7.75 (2H, d), 7.5 (1H, s), 7.3–7.45 (3H, m), 5.25 (1H, m), 4.95(2H, s), 2.1 (2H, m (obscured by solvent peak)), 1.4 (4H, m), 0.9 (3H,t).

d. (S)-8-Butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine

A solution of intermediate 1c (1.25 g, 4.65 mmole) in 20 ml THF wasadded dropwise to a stirred solution of 1M LAH in THF (16 ml). Themixture was heated to reflux for 1 hr. and then stirred at roomtemperature overnight. The mixture was then quenched by the slowaddition of a mixture of 3 g celite and 2 ml of a saturatd K₂CO₃solution. The mixture was stirred for 1 hr., and filtered solids wereextracted three times with 25 ml EtOAc. Solvents were removed underreduced pressure, and the residue was purified by flash chromatographyon silica gel using ethyl acetate:aceticacid:pyridine:water/900:54:16:30 as an eluant. The product fractionswere concentrated to oil and then taken up in ethyl acetate. Thesolution was washed with 25 ml of saturated NaHCO₃, dried over MgSO₄,filtered, and concentrated in vacuo. The product was dried on a vacuumpump to yield 190 mg (16%) of product. Mass spec. 256.2 (MH+), 278.2(MNa+).

e.7-[2-(((1,1-dimethylethoxy)carbonyl)amino)-1-oxo-3-((triphenylmethyl)thio)propyl]-8-Butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine

Dicyclohexylcarbodiimide (155 mg, 0.75 mmole) and Boc-Cys(Trt)-OH(Advanced Chemtech) were dissolved in 8 ml of THF and stirred for 5 min.The resulting dicyclohexylurea was filtered off, and the filtrate wasadded to intermediate 1d. The resulting mixture was stirred at roomtemperature for 6 hrs, concentrated to a gum, and purified by flashchromatography on silica gel using 7:3/hexanes:EtOAc as an eluant.Product fractions were combined and concentrated to a glass yielding 500mg (95%) of product. Mass spec. 701.5 (MH+), 723.5 (MNa+). NMR (300 MHz,CD₃CO₂D), 7.7 (2H, d), 7.5 (1H, s), 7.2–7.45 (18H, m), 6.05 (1H, d), 4.6(1H, t) 4.2 (2H, t), 3.95 (1H, t), 3.8 (1H, m), 2.6 (2H, m), 2.0 (2H,m(obscured by solvent)), 1.4 (9H, s), 1.2–1.4 (4H, m), 0.9 (3H, t)

f.7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine(Compound 1)

Intermediate 1e (322 mg, 0.46 mmole) was stirred with 10 ml of Reagent B(Tfa:phenol:(iPr₃SiH):H₂O/8.8:0.5:0.2:0.5) under nitrogen for 15 min.The solvents were removed under reduced pressure, and the residue wastaken up in 25 ml H₂O and washed two times with 25 ml Et₂O. The aqueouslayer was purified by reverse phase column chromatography to provide 9mg (5%) of compound 1 as a white lyophilized powder. Mass spec: 359.1(MH+).

EXAMPLE 27-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(4-fluorophenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine(Compound 2)

Compound 2 was prepared by in a manner analogous to Example 1 exceptthat 2-bromo-4′-fluoro-acetophenone was used in place of2-bromoacetophenone in step a. Mass spec. 377.2 MH+. NMR (300 MHz,CD₃CO₂D), (approximately 2 to 1 mixture of conformers observed) 7.8–8.0(2H, m), 7.6–7.8 (1H, s), 7.1–7.3 (12H, m), 5.8–6.3(1H, m), 3.5–5.3(5H,t), 3.0–3.4 (2H, m), 2.1–2.6 (2H, m), 1.3–1.7 (4H, m), 0.8–1.0 (3H, m).

EXAMPLE 37-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine(Compound 3)

Compound 3 was prepared in a manner analogous to Example 1 except that2-bromo-2′-methoxy-acetophenone was used in place of 2-bromoacetophenonein step a. Mass spec. 389.3 MH+. NMR (300 MHz, DMSO-d6), 8.2–8.8 (3H,s), 7.7–8.0 (2H, m), 7.2–7.4 (1H, m), 6.8–7.2(2H, m), 5.4–5.8 (1H,t),4.5–4.8 (1H, t), 3.7–4.5 (4H, m), 3.9(3H, s), 2.7–3.1 (2H, m), 1.8–2.1(2H, m) 1.3–1.6 (4H, m), 0.8–1.0 (3H, t).

EXAMPLE 47-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(3-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine(Compound 4)

Compound 4 was prepared in a manner analogous to Example 1 except that2-bromo-3′-methoxy-acetophenone was used in place of 2-bromoacetophenonein step a. Mass spec. 389.3 MH+. NMR (300 MHz, DMSO-d6), ),(approximately 4 to 1 mixture of conformers observed) 8.2–8.7 (3H, s),7.7–8.0 (1H, s), 7.2–7.5 (3H, m), 6.8–7.0 (2H, d), 5.4–5.8 (1H, t),4.5–4.8 (1H, t), 3.7–4.5 (4H, m), 3.8 (3H, s), 2.7–3.1 (2H, m), 1.8–2.1(2H, m) 1.2–1.6 (4H, m), 0.8–1.0 (3H, t).

EXAMPLE 57-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine(Compound 5)

Compound 5 was prepared in a manner analogous to Example 1 except that2-bromo-4′-methoxy-acetophenone was used in place of 2-bromoacetophenonein step a. Mass spec. 389.2 MH+. NMR (300 MHz, DMSO-d6), ),(approximately 6 to 1 mixture of conformers observed) 8.2–8.8 (3H, s),7.7–8.0 (1H, s), 7.5–7.8 (2H, d), 6.9–7.2 (2H, d), 5.4–5.8 (1H, t),4.5–4.8 (1H., t), 3.7–4.5 (4H, m), 3.8 (3H, s), 2.7–3.2 (2H, m), 1.8–2.1(2H, m) 1.2–1.6 (4H, m), 0.8–1.0 (3H, t).

EXAMPLE 67-(2-amino-1-oxo-3-thio-propyl)-8-(2-hydroxy-ethyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine(Compound 6)

Compound 6 was prepared in a manner analogous to Example 1 except that2-bromo-4′-methoxy-acetophenone in place of 2-bromoacetophenone in stepa. Mass spec. 347.1 MH+.

EXAMPLE 77-(2-amino-3-thio-propyl)-8-butyl-3-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine(Compound 7)

Compound 7 was synthesized according to synthetic Scheme 2 as set forthbelow:

a. Ethyl,2-((2-(((1,1-dimethylethoxy-)carbonyl-)amino-)ethyl-)amino-)-hexanoate

Boc-NHCH₂CH₂NH₂ was prepared as described by A. P. Krapcho and C. S.Kuell, Syn. Comm. 20(16):2559–2564 (1990). Boc-NHCH₂CH₂NH₂ (5.00 g,31.25 mmole), ethyl 2-bromohexanoate (5.71 ml, 31.25 mmole), and K₂CO₃(4.31 g, 31.25 mmole) were combined in 75 ml DMF and stirred at 40° C.for 1.5 hr. Solvents were removed under reduced pressure, and theresidue was then distributed between Et₂O and H₂O. The ether layer wasdried over MgSO₄ and filtered, and the solvents were removed underreduced pressure to yield 7.48 g (79%) of an oil. Mass spec. 303.0 MH+,NMR (CDCl₃), 4.9–5.1 (1H, S br), 4.1–4.4 (2H, M), 3.0–3.6 (2H, M),2.5–3.0 (2H, M), 1.9–2.2 (1H, S br), 1.3–1.8 (2H, M), 1.5 (9H, S),1.2–1.5 (7H, M), 0.8–1.0 (3H t).

b. Ethyl,2-(N-(2-(((1,1-dimethylethoxy-)carbonyl-)amino-)ethyl-)]-N-[(phenylmethoxy)carbonyl-]amino-hexanoate

Intermediate 7a (7.40 g, 24.5 mmole) was dissolved in 40 ml THF, and 10ml H₂O was then added. The mixture was cooled to 5° C., and Cbz-Cl wasadded in four portions to the mixture. The pH of the mixture wasmaintained between 8–9 by addition of 2.5N NaOH. When the reaction wascompleted, the solvents were removed under vacuum, and the residue wastaken up in EtOAc and washed with 5% citric acid solution. The solventswere removed under reduced pressure. The residue was dissolved inhexanes, filtered to remove a crystalline impurity, and dried to yield7.34 g (69%) of an oil. Mass spec. 337.2 (M-Boc)H+, 459.3 M Na+. NMR(CDCl₃), 7.2–7.6 (5H, M), 5.1–5.4 (3H, M), 3.9–4.4 (3H, M), 3.5–3.8 (1H,M), 3.1–3.5 (3H, M), 1.6–2.2 (2H, M), 1.4–1.5 (9H, S), 1.1–1.5 (7H, M),0.8–1.0 (3H t).

c. 3-Butyl-2-oxo-4-((phenylmethoxy)-carbonyl)-piperazine

Intermediate 7b (7.10 g, 16.3 mmole) was dissolved in 25 ml of9:1/Tfa:H₂O and stirred for 15 min. under nitrogen. Solvents wereremoved under reduced pressure, and the residue was taken up in EtOAc.The solution was washed with a saturated NaHCO₃ solution, dried overMgSO₄, filtered, and solvents were removed under reduced pressure. 10 mlacetic acid and 10 ml pyridine was added to the residue, and it wasrefluxed for 1 hour under nitrogen. Solvents were removed under reducedpressure, and the residue was dissolved in EtOAc and washed two timeswith 5% citric acid. The solution was dried over MgSO₄, filtered, andsolvents were removed under reduced pressure. The product wascrystallized from a solution of EtOAc/hexanes to yield 2.40 g (51%) of awhite powder. m.r.=107–108° C. Mass spec. 291.2 MH+, 313.2 M Na+. NMR(CDCl₃), 7.3–7.5 (5H, S), 7.0–7.2 (1H, S br), 5.1–5.3 (2H, Q), 4.5–4.8(1H, S br), 4.1–4.4 (1H, S br), 3.4–3.6 (1H, T), 3.1–3.4 (2H, D),1.7–2.1 (2H, M), 1.2–1.5 (4H, M), 0.8–1.0 (3H S br).

d. 3-Butyl-4-((phenylmethoxy)-carbonyl)-2-thio-piperazine

Intermediate 7c (2.85 g, 9.83 mmole) and Lawsson's reagent (2.02 g, 5.00mmole) were dissolved in 20 ml THF and heated at reflux under nitrogenfor 1.5 hours. The solution was cooled, and solvents were removed underreduced pressure. The residue was dissolved in 50 ml Et₂O and washedthree times with 25 ml of 1N NaOH. The solution was dried over MgSO₄,filtered, and solvents were removed under reduced pressure. The residuewas purified by flash chromatography on silica gel using65:35/hexanes:EtOAc as an eluant. The product fractions wereconcentrated to yield 2.19 g (73%) of an oil which crystallized.m.r.=94–96° C. Mass spec. 307.2 MH+, 329.2 M Na+. NMR (CDCl₃), 8.5–8.8(1H, S), 7.3–7.5 (5H, S br), 4.9–5.4 (3H, M), 4.0–4.5 (1H, M), 1.1–3.6(3H, M), 3.4–3.6 (1H, T), 2.2–2.4 (2H, S br), 1.7–2.0 (2H, M), 1.2–1.6(4H, S br), 0.7–1.0 (3H S br).

e.8-Butyl-3-phenyl-7-((phenylmethoxy)-carbonyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine

Intermediate 7d (1.07 g, 3.5 mmole) was dissolved in 10 ml THF.Iodomethane (2.18 ml, 35.0 mmole) was added and stirred at roomtemperature for 8 hours. Solvents were removed under reduced pressure.The residue was dissolved in 10 ml THF, and 4-methylmorpholine (771 ul,7.0 mmole) and 2-aminoacetophenone hydrochloride (686 mg, 4.00 mmole)were added to the solution. The solution was stirred overnight at roomtemperature and then refluxed for 2 hours. 15 ml acetic acid was added,and 15 ml solvent was distilled off. The solution was then refluxed for1 hour and concentrated under vacuum. The residue was purified by flashchromatography on silica gel using 70:30/hexanes:EtOAc as an eluant. Theproduct fractions were concentrated to yield 0.97 g (71%) of an oil.Mass spec. 390.3 MH+, 412.2 M Na+. NMR (CD₃CO₂D), (approximately 1:1mixture of conformers) 7.2–7.6 (11H, M), 5.6–5.8 (1H, M), 5.0–5.4 (2H,M), 4.4–4.8 (1H, M), 4.1–4.4 (1H, M), 3.9–4.1 (1H, M), 3.3–3.6 (1H, Sbr), 1.8–2.2 (obscured by solvent)(2H, M), 1.7–2.0 (2H, M), 1.1–1.6 (4H,S br), 0.7–0.9 (3H S br).

f. 8-butyl-3-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine

Intermediate 7e (1.08 g, 2.78 mmole) was dissolved in 4 ml of THF. 10 mlof 4N HCl was added, and the mixture was heated at reflux under nitrogenfor 4 hours. Solvents were removed under reduced pressure to yield asolid product which was washed with ether and dried to 740 mg. Massspec. 256 MH+.

g.8-butyl-7-(2-((1,1-dimethylethoxy-)carbonyl-)amino-1-oxo-3-(triphenylmethyl-thio)-propyl)-3-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine

Boc-Cys(Trt)-OH (2.32 g, 5.00 mmole; Advanced Chemtech) was dissolved in20 ml of THF. DCC (515 mg, 2.50 mmole) was added to this solution. Thesolution was allowed to stand for 15 min., and the DCC was filtered off.The filtrate was added to a solution of intermediate 7f (700 mg, 2.4mmole) and NMM (655 ul, 4.80 mmole) in 20 ml of THF. The solution wasstirred for two hours at room temperature, and solvents were removedunder reduced pressure. The resulting product was purified by silica gelchromatography using 70:30/hexanes:EtOAc as an eluant. The productfractions were combined and concentrated to a foam, which was dried toyield 1.47 g (87.5%) of product. Mass spec. 701.4 MH+, NMR (CD₃CO₂D),7.1–7.7 (21H, M), 6.0–6.2 (1H, M), 6.5–6.7 (1H, T), 3.4–4.4 (4H, M),2.4–2.8 (2H, M), 1.8–2.4 (2H, M) (partially obscured by solvent signal),1.4 (9H, S), 1.1–1.4 (4H, M), 0.7–1.0 (3H, M)).

h.7-butyl-6-(2-((dimethylethoxy)-carbonyl-)amino-3-(triphenylmethyl-thio)propyl-)-3-phenyl-4,5,6,7-tetrahydro-imidazo-[1,2a]piperazine

Intermediate 7 g (350 mg, 0.50 mmole) was dissolved in THf (3 ml) and 1MBH₃/THf (7 ml, 7.0 mmole) was added. The reaction was heated at refluxfor 2 hr under N₂. The solution was cooled to room temperature, and theexcess reagent was destroyed by careful addition of a solution of MeOH(8 ml) and acetic acid (2 ml). The crude product was concentrated underreduced pressure and redissolved in 3:1/acetic acid:H₂) for 1 hr. Afterremoving solvents under reduced pressure, the residue was purified byflash chromatography on silica gel using 1% HOAc/ETOAc as eluant. Theproduct fractions were combined, concentrated, and dried to 100 mg(29%). MH+ 687.5.

i.7-(2-amino-3-thio-propyl)-8-butyl-3-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine(Compound 7)

Intermediate 7h (100 mg, 0.146 mmole) was treated under nitrogen with amixture of Tfa:H2O:iPr₃SiH/93:5:2 (10 ml) for 15 min. Solvents wereremoved under reduced pressure, and the resulting solids were trituratedeight times with 4 ml of H₂O and then filtered off. The filtrate waspurified by prep HPLC to yield 45 mg (74%) of lyophilized compound 7which appeared as a 1:1 mixture of isomers on analytical HPLC. Massspec. 345.2 MH+, NMR (CD₃CO₂D), 7.4–7.7 (6H, M), 6.0–6.4 (1H, M),3.8–5.3 (5H, M), 3.0–3.4 (2H, M), 2.0–2.4 (2H, M), 1.2–1.7 (4H, M),0.9–1.0 (3H, M).

EXAMPLE 82-(1-(N-(2-amino-1-oxo-3-thiopropyl)-N-methyl)-amino-pentyl)-5-phenyl-imidazole(Compound 8)

Compound 8 was synthesized according to Scheme 3 as set forth below:

a. 5-(1-(Methylamino)-pentyl)-2-phenyl-imidazole

Intermediate 1a (1.50 g, 4.10 mmole) and LAH (50% in oil; Alfa Products,Danvers, Mass.) (1.25 g, 16.4 mmole) were combined in toluene (10 ml)and THF (5 ml) under nitrogen, and the mixture was heated to 55° C. for4 hrs. The mixture was poured into EtOAc (100 ml), and moist celite wasadded to the mixture. Solids were filtered off, and the filtrate wasdried over Na₂SO₄ and concentrated. The crude product was used withoutfurther purification.

b.5-((N-(2-(((1,1-dimethylethoxy-)carbonyl-)-amino)-1-oxo-3-(triphenylmethyl-thio)-propyl)-N-methyl-amino)-pentyl)-2-phenyl-imidazole

Boc-Cys(Trt)-OH (3.8 g, 8.2 mmole) and DIC (643 ul, 4.1 mmole) werecombined in CH₂Cl₂ (50 ml) and stirred for 0.5 hours at roomtemperature. Intermediate 8a (1.00 g, 4.1 mmole) was added and stirredat room temperature for 1 hour. Solids were filtered off and diluted to100 ml with CH₂Cl₂. The solution was washed with saturated NaHCO₃ (3×50ml) and saturated NaCl (1×50 ml), dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by flash chromatography on silicagel (120 g) using first CH₂Cl₂, and then 1% MeOH/CH₂Cl₂ as eluants.Product fractions were combined and concentrated to yield 1.36 g (46%)of product.

c.2-(1-(N-(2-amino-1-oxo-3-thiopropyl)-N-methyl)-amino-pentyl)-5-phenyl-imidazole(Compound 8)

Intermediate 8b was dissolved in 10 ml of Reagent B under nitrogen, andthe solution was stirred for 0.5 hours. Solids were filtered off, andsolvents were removed under a stream of nitrogen. The residue wastriturated with ethyl ether and purified by reverse phase HPLC to yieldcompound 8 as a white solid after lyophilization (74.1 mg, 49%). Massspec: 347.2 MH+.

EXAMPLE 92-(((2-amino-1-oxo-3-mercapto-propyl)-amino)-methyl)-5-phenyl-thiazole-4-carbonyl-methionine(Compound 9)

Compound 9 was synthesized according to Scheme 4 as set forth below.

a. Methyl, 2-amino-3-oxo-3-phenylpropionate

Schiff base (10.0 g, 39.5 mmole) was prepared as described in (O'Donnel,et al., J. Org. Chem. 47:2663 (1982). Schiff base was dissolved in THF(60 ml) and added dropwise to a stirred mixture of KOtBu (4.43 g, 39.5mmole) in THF (30 ml) which was cooled to −70° C. under nitrogen. Thesolution was stirred for 10 min. at −70° C., and the anion wastransferred to a stirred solution of benzoyl chloride (4.59 ml, 39.5mmole) in THF (50 ml) which had also been cooled to −70° C. undernitrogen. The solution was stirred for 45 min. at −70° C. and thenquenched by the addition of 4N HCl (30 ml). THF was removed underreduced pressure, and the aqueous layer was washed twice with 50 ml ofethyl ether. The solution was concentrated to a solid, and the productwas dissolved in MeOH (30 ml), and the KCl was filtered. The product wascrystallized by the addition of ether to the point of turbidity. Theproduct was filtered off and dried to yield 2.89 g (32%) of product.Mass spec. 194.1 (MH+)

b. Methyl,2-(((1,1-dimethylethoxy-)carbonyl-)glycyl)-amino-3-oxo-3-phenylpropionate

Boc-Gly-OH (3.15 g, 18.0 mmole) and NMM (1.98 ml, 18.0 mmole) werecombined in THF (50 ml) and the solution was cooled to −20° C. iBuCOCl(2.34 ml, 18.0 mmole) was added to the solution, and the mixture wasstirred for 5 min. at −20° C. Intermediate 9a (4.13 g, 18.0 mmole) andNMM (1.98 ml, 18.0 mmole) was added to the solution which was stirredvigorously while returning to room temperature. The solution wasconcentrated under reduced pressure, and the residue was dissolved inEtOAc (50 ml) and washed once with H₂O, once with 5% citric acidsolution, and once with saturated NaCl solution. The solution was driedover MgSO₄, filtered, and concentrated under reduced pressure. Furtherpurification was accomplished by flash chromatography on silica gelusing 1:1/hexanes:EtOAc as an eluant. Product fractions were combinedand concentrated to yield 3.28 g (52%) of product. Mass spec. 373.2 MNa+

c. Methyl,2-(((1,1-dimethylethoxy-)carbonyl-)-amino)-methyl-5-phenyl-thiazole-4-carboxylate

Intermediate 9b (3.10 g, 8.86 mmole) and Lawesson's reagent (3.6 g, 8.9mmole; Aldrich Chem. Co., St. Louis, Mo.) were combined in THF (30 ml)and heated to reflux for 1 hour. Solvents were removed under a stream ofnitrogen, and the residue was purified by flash chromatography on silicagel using 1:1/hexanes:EtOAc as an eluant. Product fractions werecombined and concentrated under reduced pressure to yield 2.21 g (72%)of product. Mass spec. 349.0 MH+, 371.2 MNa+.

d.2-(((1,1-dimethylethoxy-)carbonyl-)-amino)-methyl-5-phenyl-thiazole-4-carbonyl-methioninemethyl ester

Intermediate 9c was dissolved in methanol (5 ml), and an aqueoussolution of NaOH (344 mg, 8.61 mmole) in minimum of H₂O was added to thesolution. The solution was stirred at 40° C. for 1 hour, and thesolvents were removed under reduced pressure. The residue wasdistributed between EtOAc (20 ml) and 5% citric acid (20 ml). The EtOAclayer was dried over MgSO₄, filtered, and concentrated under reducedpressure. The residue was dissolved in THF (10 ml), and HOSu (330 mg,2.87 mmole), HCl-Met-OMe (573 mg, 2.87 mmole), NMM (316 mg, 2.87 mmole)and DCC (591 mg, 2.87 mmole) were added to the solution. The mixture wasstirred at room temperature overnight, filtered, and concentrated underreduced pressure. The residue was taken up in EtOAc (25 ml), and washedonce in 5% citric acid solution and twice in a saturated NaHCO₃solution. The solution was dried over MgSO₄, filtered, and concentratedunder reduced pressure to yield 590 mg (43%) of product. Mass spec.502.2 MNa+, 480.4 MH+

e.2-(((2-(((1,1-dimethylethoxy)-carbonyl)-amino)-1-oxo-3-(triphenylmethyl-thio)-propyl)-amino)-methyl)-5-phenyl-thiazole-4-carbonyl-methioninemethyl ester

Intermediate 9d (590 mg, 1.23 mmole) was treated with Reagent B (10 ml)for 15 min at room temperature under nitrogen. Solvents were removedunder reduced pressure. The residue was triturated twice with 25 ml Et₂Oand decanted. The residue was then dissolved in THF (10 ml) and added tothe mixed anhydride generated from Boc-Cys(Trt)-OH (570 mg, 1.23 mmole),NMM (135 ul. 1.23 mmole) and iBuOCOCl (160 ul, 1.23 mmole) at −20° C.under nitrogen over 5 min. NMM (135 ul, 1.23 mmole) was added to themixture which was then allowed to warm to room temperature. Solventswere removed under reduced pressure. The residue was taken up in EtOAc(25 ml) and washed with 25 ml of H₂O and 25 ml of 5% citric acidsolution. The solution was dried over MgSO₄ and concentrated to yield1.01 g (100%) of a white foam.

f.2-(((2-amino-1-oxo-3-mercapto-propyl)-amino)-methyl)-5-phenyl-thiazole-4-carbonyl-methionine(Compound 9)

Intermediate 9e (250 mg, 0.30 mmole) was dissolved in MeOH (2 ml). NaOH(40 mg), dissolved in a minimum of H₂O, was added to the solution. Thesolution was stirred overnight at room temperature. Solvents wereremoved under reduced pressure and the residue was dissolved in reagentB (10 ml). The solution was stirred for 15 min. at room temperatureunder nitrogen and then concentrated under reduced pressure. The residuewas purified by reverse phase HPLC. Product fractions were combined andlyophilized to yield 32 mg (20%) of compound 9 as a white solid. Massspec 469 MH+.

EXAMPLE 10bis-1,1′-[2-amino-3-(8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine-6-yl)-3-oxo]propyldisulfide (Compound 10)

Intermediate 3e (300 mg, 0.41 mmole) was dissolved in methanol, and H₂O(0.3 ml) was added. A solution of iodine (104 mg, 0.41 mmol) in methanol(3 ml) was added, and the mixture was stirred for 2 hours. The solventswere removed under reduced pressure, and the residue was triturated withhexanes (2×5 ml). The residue was then dissolved in ETOAc (5 ml) andwashed with 5% Na₂S₂O₃ solution (10 ml). The organic layer was driedover Na₂SO₄, filtered, and concentrated to a glass.

The glass was treated with 93:5:2/Tfa:H₂O:iPr₃SiH for 15 minutes underN₂. The solvents were removed under reduced pressure, and the residuewas purified by RP HPLC and lyophilized. Yield=48 mg (25%). Mas spec.775.4 MH+, 388.5 M^(2H++), NMR (DMSO-d₆), (approx. 5:1 mixture ofconformers) 8.5–9.0 (3H,S), 8.0–8.2 (1H,d), 7.5–7.7 (1H,S), 7.1–7.3(1H,t), 7.0–7.1 (1H,d), 6.9–7.1 (1H, t), 5.2–5.6 (1H,t), 4.8–5.0 (1H,t),3.6–4.7 (1H,M), 3.8–4.0 (3H,S), 3.2–3.5 (2H,M), 1.8–2.2 (2H,M), 1.2–1.7(4H, M), 0.8–1.0 (3H, t).

EXAMPLE 117-(2-amino-1-oxo-3-thio-propyl)-2-(2-methoxyphenyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine(Compound 11)

Compound 11 was prepared in a manner analogous to Example 3 exceptBoc-L-Leucine was used in place of Cbz-(L)-Norleucine in step a and theBoc group was cleaved with a 9:1/Tfa:H2) mixture instead of by catalytichydrogenation in step c. Mass spec. 389.1 MH+. NMR (300 MHz, DMSO-d₆)8.6–8.8 (3H, s), 8.1–8.2 (1H, d), 7.9–8.1 (1H, S), 7.3–7.5 (1H, t),7.1–7.3 (1H, d), 7.0–7.1 (1H, T), 5.9–6.1 (1H, d), 4.7–4.8 (1H, S),4.5–4.7 (1H, d), 4.3–4.4 (1H, d), 4.1–4.3 (1H, t), 3.9–4.0 (3H, S),3.8–4.0 (1H, T), 3.3–3.5 (1H, t), 2.8–3.1 (2H, M), 1.9–2.2 (2H, M),1.7–1.8 (1H, M), 1.0–1.2 (3H, t), 0.8–1.0 (3H, t).

EXAMPLE 12bis-1,1′-[2-amino-3-(2-(2-methoxyphenyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydro-imidazo[1,2a]piperazine-7-yl)-3-oxo]propyldisulfide (Compound 12)

Compound 12 was prepared in a manner analogous to Example 10 exceptintermediate lie was used in place of intermediate 3e. Mass. spec 388.5M2H++, 775.4 MH+. NMR (300 MHz, DMSO-d₆) 8.7–9.2 (3H, S), 8.1–8.2 (1H,d), 7.9–8.1 (1H, S), 7.3–7.5 (1H, t), 7.1–7.3 (1H, d), 7.0–7.2 (1H, t),5.9–6.1 (1H, d), 4.8–5.0 (1H,S), 4.5–4.7 (1H, d), 4.3–4.5 (1H, d),4.1–4.4 (1H, t), 3.8–4.1 (1H,M), 3.8–4.0 (3H, S), 3.2–3.5 (2H, M),1.8–2.2 (2H, M), 1.7–1.9 (1H, M), 1.0–1.2 (3H, d), 0.8–1.0 (3H, d).

EXAMPLE 137-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-ethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine(Compound 13).

a. Intermediate 3c (2.54 g, 8.50 mMole) was dissolved in THF (15 ml) anda 1M solution of borane in THF (34.0 ml, 34.0 mMole) was added dropwiseover 10 minutes at room temperature. The mixture was refluxed for 2hours and allowed to stand at room temperature overnight. A solution of4 N HCl (25 ml) was added dropwise and the resulting mixture was heatedat reflux for a hour. The mixture was concentrated to H₂O, made basic bycareful addition of solid NaHCO₃, and extracted with EtOAc (2×25 ml).The EtOAc layers were dried over Na₂SO₄, filtered, and concentrated toan oil. A solution of 5% HCl (25 ml) was added, and the mixture wasconcentrated to a solid. The solid was recrystallized from methanol andethyl ether to yield 2.72 g (89.5%) of the dihydrochloride salt. Massspec. 286.2. M.R.=242–247° C.

b. Intermediate 13a (850 mg, 2.37 mMole) was distributed between CH₂Cl₂and saturated NaHCO₃ solution, the CH₂Cl₂ layer was dried over Na₂SO₄,and filtered. A 1M solution of BBr₃ in CH₂Cl₂ was added and theresulting mixture was heated at reflux for 1 hour. The reaction wascooled and poured onto saturated NaHCO₃ solution (25 ml). The CH₂Cl₂layer was dried over Na₂SO₄ and filtered. Di-(tert)-butyldicarbonate(523 mg, 2.40 mMole) was added and the mixture was stirred at roomtemperature over the weekend. Solvents were evaporated, and theresulting oil was purified by column chromatography on silica gel using70:30/hexanes:Ethyl acetate as eluant. Yield=700 mg (80%) of a clearoil. Mass spec. 372.2 (MH+). NMR

c. Protected intermediate (13b) (600 mg, 1.62 mMole) was dissolved inTHF (10 ml) and added dropwise to a solution of NaH (60% in oil, 120 mg,3.0 mMole) in THF (10 ml) at room temperature under N₂. The reaction wasstirred 15 minutes and ethyl iodide (400 ul, 5.00 mMole) was added. Themixture was stirred overnight at room temperature then concentratedunder reduced pressure. Saturated NaHCO₃ solution (10 ml) was added, andthe product was extracted with ethyl ether (2×20 ml). The ether wasevaporated, and the residue was purified by column chromatography onsilica gel using 3:1/hexanes:ethyl acetate as eluant. Yield=410 mg (64%)of the ether. Mass spec. 400.3 (MH+). M.R.=103–109° C.

d. Intermediate (13c) was treated with 90% TFA/H₂O (2 ml) for 0.5 hoursand concentrated to remove the BOC group. Coupling withBoc-(L)-Cys(Trt)-OH and deprotection were accomplished in a manneranalogous to example 1e and 1f, respectively, to yield compound 13. Massspec. 403.2 (MH+). NMR (300 MHz, DMSO-d6) 8.4–8.7 (3H, broad s), 7.9–8.0(1H, s), 7.75–7.9 (1H, d), 7.15–7.3 (1H, t), 7.0–7.1 (1H, d), 6.85–7.0(1H, t), 5.7–5.85 (1H, m), 4.65–4.8 (1H, broad s), 4.45–4.6 (1H, d),4.3–4.4 (1H, d,d), 4.1–4.25 (1H, m), 3.75–3.95 (1H, m), 3.1–3.3 (1H, m),2.8–3.1 (2H, m), 1.9–2.15 (2H, m), 1.2–1.5 (4H, m), 0.8–1.0 (3H, t).

EXAMPLE 147-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-hydroxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine (Compound 14).

a. Intermediate 13a (179 mg, 0.50 mMole) was distributed between CH₂Cl₂and saturated NaHCO₃ solution, the CH₂Cl₂ layer was dried over Na₂SO₄,and filtered. A 1M solution of BBr₃ in CH₂Cl₂ was added, and theresulting mixture was heated at reflux for 1 hour. The reaction wascooled and poured onto saturated NaHCO₃ solution (25 ml). The CH₂Cl₂layer was dried over Na₂SO₄, filtered, and stripped to yield crudede-methylated product as a gum. This material was used without furtherpurification.

b. Coupling of (14a) with Boc-(L)-Cys(Trt)-OH and deprotection wereaccomplished in a manner analogous to example 1e and 1f, respectively,to yield compound 14. Mass spec. 403.2 (MH+). NMR (300 MHz, DMSO-d6)8.55–8.8 (3H, broad s), 8.1–8.2 (1H, d), 7.85–7.95 (1H, s), 7.35–7.45(1H, t), 7.15–7.25 (1H, d), 7.0–7.15 (1H, t), 5.85–6.0 (1H, d,d),4.65–4.8 (1H, broad s), 4.55–4.7 (1H, d,d), 4.15–4.3 (2H, q), 4.1–4.2(1H, m), 3.8–3.95 (1H, m), 3.3–3.5 (1H, t), 2.15–2.3 (1H, m), 1.95–2.15(1H, m), 1.4–1.5 (3H, t), 1.2–1.5 (4H, m), 0.8–1.0 (3H, t).

EXAMPLE 152-(1-(N-(2-amino-1-oxo-3-thiopropyl)-N-Methyl)-amino-pentyl-5-(2-methoxyphenyl)-imidazole(Compound 15)

Compound 15 was prepared in a manner analogous to example 8 except2-Bromo-2′-methoxyacetophenone was used in place of 2-Bromoacetophenonein step 1a. Mass Spec. 377.1 MH+. NMR (300 MHz, CD3CO2D) 7.8–7.9 (1H,s), 7.65–7.75 (1H, d,d), 7.4–7.55 (1H, m), 7.14–7.2 (1H, d), 7.05–7.14(1H, t), 5.6–5.8 (1H, t), 4.8–4.9 (1H, t), 3.9–4.0 (3H, s), 3.25–3.35(3H, s), 3.05–3.25 (2H, m), 2.2–2.4 (2H, m), 1.2–1.6 (4H, m), 0.8–1.0(3H, t).

EXAMPLE 16bis-1,1′-[2-(1-(N-(2-amino-1-oxo-3-thiopropyl)-N-methylamino)-pentyl]-5-(2-methoxyphenyl)imidazole]disulfide(Compound 16)

Compound 16 was prepared in a manner analogous to example 10 exceptcompound 15 in place of intermediate 3e. Mass spec. 751.5 MH+. NMR (300MHz, CD3CO2D) 7.75–7.85 (1H, s), 7.65–7.75 (1H, d,d), 7.35–7.5 (1H, m),7.1–7.2 (1H, d), 7.0–7.1 (1H, t), 5.5–5.6 (1H, t), 4.8–4.95 (1H, t),3.9–4.1 (3H, s), 3.3–3.5 (2H, m), 3.2–3.3 (1H, s), 2.2–2.4 (2H, m),2.0–2.2 (acetate signal), 1.2–1.6 (4H, m), 0.8–1.0 (3H, t).

EXAMPLE 177-(2-amino-1-oxo-3-thiopropyl)-8-(2-methylpropyl)-2-(1-naphthyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine(Compound 17).

a. 1′-Acetonaphthone (10.2 g, 60.0 mMole) and 0.1 ml of concentrated HClwere dissolved in acetic acid (100 ml) and bromine (9.6 g, 60.0 mmole)were added dropwise with stirring over a three hour period. The reactionwas concentrated under reduced pressure and dried to constant weight.The product was used without further purification.

b. Compound 17 was prepared in a manner analogous to example 1 exceptCbz-(L)-Leucine was used in place of Cbz-(L)-Norleucine, intermediate17a was used in place of 2-Bromoacetophenone in step 1a, and 1M BH₃/THFwas used for reduction of lactam intermediate in step d. Mass spec.409.2 MH+. NMR (300 MHz, DMSO-d6) 8.5–8.9 (3H, s), 8.1–8.25 (1H, d),7.9–8.15 (3H, m), 7.7–7.8 (1H, d), 7.5–7.7 (3H, m), 5.8–6.1 (1H, d),4.7–4.85 (1H, s), 4.55–4.75 (1H, d), 4.2–4.45 (2H, m), 3.85–4.05 (1H,m), 3.0–3.4 (10H, H2O), 2.9–3.1 (2H, q), 1.9–2.2 (1H, t), 1.7–1.9 (2H,m), 1.0–1.2 (3H, d), 0.8–1.0 (3H, d).

EXAMPLE 187-(2-amino-1-oxo-3-thiopropyl)-8-(1-methyl-propyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine(Compound 18).

Compound 18 was prepared in a manner analogous to example 3 exceptCbz-(L)-Isoleucine was used in place on Cbz-(L)-Norleucine in step a.Mass spec. 389.3 MH+. NMR (300 MHz, DMSO-d6) 8.5–8.9 (3H, s), 8.05–8.2(1H, d), 7.9–8.05 (1H, s), 7.35–7.5 (1H, t), 7.15–7.25 (1H, d), 7.0–7.15(1H, t), 5.65–5.85 (1H, d), 4.65–4.8 (1H, s), 4.5–4.65 (1H, d,d),4.3–4.45 (1H, d,d), 3.9–4.0 (3H, s), 3.8–4.0 (1H, m), 3.2–3.7 (8H, H2O),2.8–3.0 (2H, m), 2.2–2.4 (1H, m), 1.4–1.6 (1H, m), 1.15–1.35 (1H, m),1.0–1.15 (3H, d), 0.8–0.95 (3H, t).

EXAMPLE 19 bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)disulfide (Compound 19).

Compound 19 was prepared in a manner analogous to example 10 exceptcompound 17 was used in place of intermediate 3e. Mass spec. 815.5 MH+.NMR (300 MHz, DMSO-d6) 8.7–9.2 (3H, s), 8.15–8.3 (1H, s), 8.0–8.1 (2H,m), 7.85–8.0 (1H, s), 7.7–7.8 (1H, d), 7.5–7.7 (3H, m), 5.8–6.0 (1H, s),4.8–5.0 (1H, s), 4.5–4.54 (1H, d), 4.4–4.5 (1H, d), 4.2–4.4 (1H, t),3.9–4.1 (1H, t), 3.0–3.9 (12H, m H2O obscures signal), 2.0–2.2 (1H, t),1.7–2.0 (2H, m), 1.0–1.2 (3H, d), 0.85–1.0 (3H, d).

EXAMPLE 20bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(methoxy-phenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide(Compound 20).

Compound 20 was prepared in a manner analogous to example 10 exceptcompound 18 was used in place of intermediate 3e. Mass spec. 775.5 MH+.NMR (300 MHz, DMSO-d6) 8.7–9.0 (3H, s), 8.05–8.15 (1H, d), 7.9–8.1 (1H,s), 7.35–7.5 (1H, t), 7.15–7.25 (1H, d), 7.0–7.15 (1H, t), 5.65–5.85(1H, d), 4.8–5.0 (1H, s), 4.45–4.6 (1H, d), 4.35–4.5 (1H, d), 4.2–4.35(1H, m), 3.8–4.1 (1H, m), 3.8–3.9 (3H, s), 3.4–3.8 (10H, H2O), 3.2–3.4(2H, d), 2.2–2.4 (1H, m), 1.4–1.65 (1H, m), 1.15–1.35 (1H, m), 1.0–1.15(3H, d), 0.8–0.95 (3H, t).

EXAMPLE 21S-(dimethylethyl)-S′-[2-amino-3-oxo-3(8-butyl-2-(2-methoxyphenyl;)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)propyl]disulfide(Compound 21)

Compound 21 was prepared in a manner analogous to example 3 except thatFmoc-(L)-Cys(tBuS-)OH was used in step e and final deprotection wasaccomplished by treatment with tris(aminoethyl)amine (1.5 ml per mmole)in CH₂Cl₂ (10 ml per mmole) for 0.5 hour at room temperature. Theproduct was purified by preparative reverse phase column chromatographyto provide pure compound 21. Mass spec. 477.3 MH+. NMR (300 MHz,DMSO-d6, 90° C.) 8.0–8.1 (1H, d), 7.4–7.5 (1H, s), 7.1–7.3 (1H, t),7.0–7.1 (1H, d), 6.9–7.0 (1H, t), 5.4–5.55 (1H, s), 4.3–4.7 (1H, m),4.1–4.3 (1H, d), 3.8–4.1 (7H, m), 3.0–3.2 (2H, m+H2O), 2.8–2.9 (1H,d,d), 2.1–2.3 (2H, m), 1.7–2.1 (2H, m), 1.2–1.7 (13H, m), 0.8–1.0 (3H,t).

EXAMPLE 227-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine(Compound 22)

a. 2′-Methylacetophenone (25.0 g, 186 mMole) was dissolved in glacialacetic acid (250 ml) and concentrated HCl (250 uL) was added followed bya dropwise addition of bromine (9.6 ml, 186 mMole) over 15 minutes. Themixture was stirred 3 hours and then concentrated under reducedpressure. The residue was taken up in ethyl ether and washed withsaturated NaHCO₃ solution. The ether layer was dried over Na₂SO₄,filtered, and concentrated to yield 38.0 g, (96%) of crude2-bromo-2′-methylacetophenone which was used without furtherpurification.

b. Compound 22 was prepared in a manner analogous to example 3 except2-bromo-2′-methylacetophenone was used in place of2-bromo-2′-methoxyacetophenone in step a. Mass spec. 373.2 MH+. NMR (300MHz, DMSO-d6) 8.6–8.8 (3H, s), 7.9–8.0 (1H, s), 7.6–7.75 (1H, d),7.3–7.5 (3H, m), 5.8–6.0 (1H, d,d), 4.7–4.8 (1H, s), 4.55–4.7 (1H, d),4.3–4.44 (1H, d,d), 4.1–4.3 (1H, m), 3.8–4.0 (1H, m), 3.4–3.55 (1H, t),2.85–3.1 (2H, m), 2.4–2.5 (3H, s), 2.0–2.3 (2H, m), 1.2–1.6 (4H, m),0.8–1.0 (3H, t).

EXAMPLE 23bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide(Compound 23)

Compound 23 was prepared in a manner analogous to example 10 exceptcompound 23 was used in place of intermediate 3e. Mass spec. 743.4 MH+.NMR (300 MHz, DMSO-d6, 90° C.) 7.6–7.8 (1H, d), 7.2–7.3 (1H, s), 7.0–7.2(3H, m), 5.3–5.6 (1H, broad s), 4.3–4.8 (1H, broad s), 3.5–4.2 (4H, m),3.0–3.3 (2H, broad s), 2.8–3.0 (1H, m), 2.4–2.5 (3H, s), 2.1–2.4 (2H,broad s), 1.7–2.1 (2H, m), 1.2–1.7 (4H, m), 0.8–1.0 (3H, t).

EXAMPLE 247-(2-amino-1-oxo-3-thiopropyl)-8-(1,1-dimethylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1,2a]pyrazine(Compound 24)

Compound 24 was prepared in a manner analogous to example 3 exceptBoc-(L)-t-Leucine was used in place of Cbz-(L)-Norleucine in step a anddeprotection was accomplished in step c by treatment withtrifluoroacetic acid for 0.5 hours. Mass spec. 389.3 MH+. NMR (300 MHz,DMSO-d6) 8.5–8.8 (3H, broad s), 7.95–8.1 (1H, d), 7.9–8.0 (1H, s),7.3–7.5 (1H, t), 7.1–7.25 (1H, d), 7.0–7.15 (1H, t), 5.55–5.7 (1H, s),4.65–4.8 (1H, broad s), 4.5–4.6 (1H, m), 4.35–4.5 (1H, m), 4.1–4.3 (1H,m), 3.9–4.1 (1H, m), 3.85–3.95 (3H, s), 3.3–3.4 (1H, t), 2.7–34.1 (2H,m), 1.0–1.2 (9H, s).

EXAMPLE 257-(2-amino-1-oxo-3-thiopropyl)-8-(1-methyl-propyl)-2-(2-(phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine(Compound 25)

a. Intermediate 18d (3.36 g, 11.8 mMole) was dissolved in 10 ml CH₂Cl₂and a 1M solution of BBr₃ in CH₂Cl₂ (47 ml) was added dropwise. Themixture was heated at reflux for 2 hours, cooled and poured intosaturated NaHCO₃ solution (25 ml). The aqueous layer was extracted 3times with CH₂Cl₂ (60 ml), dried over Na₂SO₄, filtered, and concentratedto 30 ml. Di-(tert) butyldicarbonate (2.57 g, 11.8 mMole) was added, andthe reaction stirred at room temperature overnight. The crude productwas purified by column chromatography on silica gel using 1:1/ethylacetate:hexanes as eluant. The yield was 3.31 g (75%) of white solidproduct.

b. Intermediate 25a (850 mg, 2.29 mMole) was dissolved in THF (20 ml)that contained sodium hydride (96.1 mg, 2.4 mMole) and the mixture wastreated with benzyl bromide (292 uL, 2.4 mMole) under N₂ at roomtemperature. The reaction was stirred overnight at room temperature andconcentrated. The residue was partitioned between CH₂Cl₂ (30 ml) and H₂O(15 ml). The CH₂Cl₂ layer was dried over Na₂SO₄, filtered, andconcentrated. Crystallization from ethyl ether and hexanes yielded 887mg (83.7%) of the product.

c. Intermediate 25b (887 mg, 1.92 mMole) was treated with 90% Tfa/H₂O(50 ml) for 15 minutes at room temperature under N₂. Solvents wereremoved under reduced pressure and the residue was distributed betweenCH₂Cl₂ and saturated NaHCO₃ solution. The CH₂Cl₂ layer was dried overNa₂SO₄ solution, filtered and concentrated. The crude intermediate wasacylated in a manner analogous to example 1, step 1e, and thendeprotected in a manner analogous to example 1, step f. Mass spec. 465.3MH+. NMR (300 MHz, DMSO-d6) 8.3–8.8 (3H, broad s), 8.0–8.1 (1H, d,d),7.8–8.0 (1H, s), 7.45–7.55 (2H, m), 7.3–7.45 (4H, m), 7.15–7.3 (1H, d),7.0–7.15 (1H, t), 5.6–5.8 (1H, d), 5.3–5.4 (2H, s), 4.65–4.8 (1H, broads), 4.45–4.6 (1H, m), 4.25–4.4 (1H, m), 4.1–4.25 (1H, m), 3.75–3.95 (1H,m), 3.25–3.4 (1H, t), 2.8–3.0 (2H, m), 2.15–2.4 (1H, m), 1.4–1.6 (1H,m), 1.1–1.35 (1H, m), 0.95–1.1(3H, d), 0.8–1.0 (3H, t).

EXAMPLE 267-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexyl-methyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine(Compound 26).

a. A solution of H-(L)-Phe-OH (10.0 g, 60.6 mMole) in acetic acid (60ml) and 5% aqueous HCl (60 ml) was hydrogenated over PtO₂ (430 mg) untilhydrogen was no longer consumed. Solvents were removed under reducedpressure, and the residue was dissolved in methanol (50 ml) and H₂O (20ml). A 10% NaOH solution was added with vigorous stirring to pH=4.4, thesolution was cooled, and the product was filtered off and washed withH₂O.

b. Crude intermediate 26a (60.6 mMole) was suspended in 100 ml H₂Ocontaining K₂CO₃ (8.36 g, 60.6 mMole), and a solution of Cbz-Osu (15.1g, 60.6 mMole) in CH₃CN (150 ml) was added with vigorous stirring for 45minutes at room temperature. The CH₃CN was distilled off at reducedpressure and the aqueous layer was washed with ethyl ether. The aqueouslayer was acidified with concentrated HCl to pH=1 and the productextracted with ethyl acetate (2×50 ml). The ethyl acetate layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure toyield 17.27 g (93%) of Cbz-(L)-cyclohexylalanine (26b).

c. Compound 26 was prepared in a manner analogous to example 3 exceptCbz-(L)-Cyclohexylalanine (26b) was used in place of Cbz-(L)-Norleucinein step a. Mass spec. 429.3 (MH+). NMR (300 MHz, DMSO-d6) 8.6–8.9 (3H,s), 8.1–8.3 (1H, d,d), 7.9–8.1 (1H, s), 7.35–7.5 (1H, m), 7.15–7.25 (1H,d), 7.05–7.15 (1H, t), 6.0–6.1 (1H, t), 4.7–4.8 (1H, m), 4.55–4.7 (1H,m), 4.3–4.45 (1H, m), 4.1–4.3 (1H, m), 3.9–4.0 (3H, s), 3.8–3.95 (1H,m), 3.35–3.5 (1H, t), 2.8–3.1 (2H, m), 2.05–2.2 (1H, d), 1.9–2.1 (2H,t), 0.8–1.7 (10H, m).

EXAMPLE 277-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine(Compound 27).

Compound 27 was prepared in a manner analogous to example 3 exceptCbz-(L)-Valine was used in place of Cbz-(L)-Norleucine in step a. Massspec. 375.1 MH+. NMR (300 MHz, DMSO-d6) 8.6–8.8 (3H, broad s), 8.1–8.3(1H, d), 8.0–8.1 (1H, s), 7.35–7.5 (1H, t), 7.15–7.25 (1H, d), 7.05–7.15(1H, t), 5.6–5.8 (1H, d), 4.65–4.8 (1H, broad s), 4.5–4.7 (1H, m),4.3–4.45 (1H, m), 4.1–4.3 (1H, m), 3.9–4.0 (3H, s), 3.8–3.95 (1H, m),3.35–3.5 (1H, t), 2.8–3.05 (2H, m), 2.5–2.7 (1H, m), 1.1–1.2 (3H, d),0.9–1.05 (3H, d).

EXAMPLE 28bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydroimidazo[1,2a]]pyrazine]disulfide(Compound 28).

Compound 28 was prepared in a manner analogous to example 10 exceptcompound 27 was used in place of intermediate 3e. Mass spec. 747.4 MH+.NMR (300 MHz, DMSO-d6) 8.8–9.0 (3H, broad s), 8.05–8.2 (1H, d), 7.9–8.1(1H, s), 7.35–7.5 (1H, t), 7.15–7.25 (1H, d), 7.0–7.15 (1H, t),5.55–5.75 (1H, broad s), 4.8–5.0(1H, broad s), 4.45–4.65 (1H, m),4.35–4.5 (1H, m), 4.2–4.35 (1H, m), 3.85–3.95 (3H, s), 3.9–4.05 (1H, m),3.2–3.4 (2H, d), 2.45–2.65 (1H, m partially obscured by solvent),1.05–1.2 (3H, d), 0.9–1.05 (3H, d).

EXAMPLE 297-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2(2-hydroxy-6-methoxyphenyl)-5,6,7,8-tetrahydro[1,2a]pyrazine(Compound 29).

a. Bromine (3.19 ml, 61.9 mMole) was added dropwise to a mixture of2′,6′-dimethoxysacetophenone (11.15 g, 61.9 mmole) and concentrated HCl(100 uL) in acetic acid (50 mL) over 20 minutes. The reaction wasstirred at room temperature for 2 hours, and the solvents wereevaporated under reduced pressure. The residue was dissolved in ethylacetate (100 ml) and washed with saturated NaHCO₃ solution (100) andwith saturated NaCl solution (100 ml). The ethyl acetate layer was driedover Na₂SO₄, filtered, and concentrated to an oil (14.9 g).Crystallization from ethyl acetate and hexanes yields 4.87 g (30%) of2-bromo-2′,6′-dimethoxyacetophenone (29a).

b. Compound 29 was prepared in a manner analogous to example 3 except2-bromo-2′,6′-dimethoxyacetophenone (29a) was used in place of2-bromoacetophenone in step a. One methyl ether group is cleavedefficiently during BH₃ reduction of lactam 29d. Mass spec. 405.3.

EXAMPLE 30bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(1,1-dimethylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide(Compound 30)

Compound 30 was prepared in a manner analogous to example 10 exceptcompound 24 was used in place of intermediate 3e. Mass spec. 775.5(MH+). NMR (300 MHz, DMSO-d6) 8.7–9.1 (3H, broad s), 8.0–8.1 (1H, d),7.8–8.0 (1H, s), 7.3–7.5 (1H, t), 7.1–7.2 (1H, d), 7.0–7.1 (1H, t),5.55–5.65 (1H, s), 4.8–5.0 (1H, s), 4.4–4.6 (2H, m), 4.2–4.4 (1H, m),3.9–4.1 (1H, m), 3.8–4.0 (3H, s), 3.2–3.4 (2H, d), 1.0–1.2 (9H, s).

EXAMPLE 312-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydro-7-((thiazolidin-4-yl)carbonyl)-imidazo[1,2a]pyrazine(Compound 31)

Compound 31 was prepared in a manner analogous to example 18 exceptBoc-(L)-thiaproline was used for the coupling in step e. Mass spec.401.3 (MH+). NMR (300 MHz, DMSO-d6, 90

C) 8.0–8.2 (1H, d), 7.85–8.0 (1H, s), 7.3–7.5 (1H, t), 7.15–7.25 (1H,d), 7.05–7.15 (1H, t), 5.7–5.85 (1H, d), 4.75–5.0 (1H, s), 4.45–4.7 (1H,m), 4.3–4.45 (2H, m), 4.15–4.3 (2H, m), 3.9–4.0 (3H, s), 3.8–3.95 (1H,m), 3.4–3.6 (1H, t), 3.1–3.25 (1H, m), 2.25–2.45 (1H, m), 1.4–1.6 (1H,m), 1.15–1.4 (1H, m), 1.0–1.23 (3H, t), 0.8–1.0 3H, t).

Antiproliferative Activity of Farnesyl-transferase Inhibitors on HumanTumoral Cells

The assays were performed using either A-427 lung carcinomas (expressingmutated Ki-ras gene), HT-29 colon adenocarcinomas (expressing wild typeras gene), Calu-1 lung carcinomas (expressing mutated Ki-ras gene), andMIA-PaCa pancreatic cancer cells (expressing mutated Ki-ras gene). Thesetumoral cells were seeded on 96 well plates at day 0 and maintained at37° C. in 5% CO₂ atmosphere. At day 1, cells were treated with increasedconcentrations of test compounds ranging from 0 to 100 μM for 96 hrs. Atthe end of this period, the quantification of cell proliferation wasevaluated by the calorimetric assay based on the cleavage of thetetrazolium salt WST-1 by mitochondrial dehydrogenases in viable cellsleading to the formazan formation (Cell Proliferation Reagent WST-1 Kit,Boehringer Mannheim, Germany). These experiments, done in octuplicate,were repeated twice. The results, shown in Table I, depict theconcentration range (μM) of test compound required to inhibitproliferation as compared to control cells in which no test compound wasadded.

TABLE I CELL TYPE COMPOUND A-427 HT-29 Calu-1 MIA PaCa-2 3 6.25–12.512.5 10–30 12.5–25   4 12.5–25    50–100 10–30 5 6.25–25    50–10012.5–25   6  50–100 8 12.5–25   25 · 50 25–50 10 3.12–125  25–50  3–1011  6.25–12.25  50–100  30–100 12 3.12–6.25 50 10–30 13 6.25–12.5 25–5012.5–50   14 3.12–12.5  50–100 10–30 15 6.25–12.5 25–50 12.5–25   163.12–12.5 25–50 12.5–25   17 6.25–12.5   6–12.5 12.5–25   18 6.25 50–100 12.5–25   19 0.78–1.56 6.25–12.5 20 0.78  50–100 6.25–12.5 12.521 12.5–25   25–50 25–50 22 6.25–12.5 12.5–25   23 3.12–6.25 12.5–25  6.25–12.5 24 6.25–12.5  50–100 25–50 25 0.78–1.56 12.5–25   12.5–25  6.25–12.5 26 0.39–1.56 12.5 12.5–25   6.25–12.5 27 6.25  50–10012.5–25   28 12.5–25    50–100 29 3.12–6.25 25–50 6.25–12.5 30 3.12–6.2525–50 12.5–25   31 25–50

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the claims.

1. A compound having the formula (I):

wherein: R₁ is H, lower alkyl, cycloalkylthio, or lower alkylthio, or,together with R₂, form —CH₂— or —C(CH₃)₂—; each of R₂ and R₃,independently, is H or lower alkyl; R₄ is H₂ or O; R₅ is H, orsubstituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, cycloalkenyl loweralkyl, aryl, aryl lower alkyl, heterocyclyl, or heterocyclyl loweralkyl, wherein the substituent is lower alkyl, —O—R₁₀, —S(O)_(m)R₁₀(where m is 0, 1, or 2), —N(R₁₀)(R₁₁), —N—C(O)—R₁₀, —NH—(S₂)—R₁₀;—CO₂—R₁₀, —C(O)—N(R₁₀)(R₁₁), or —(SO₂)—N(R₁₀)(R₁₁); each of R₆ and R₇,independently, is H, —C(O)NHCHR₁₃CO₂R₁₄, or substituted or unsubstitutedlower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyloalkenyl,cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, orheterocyclyl lower alkyl, wherein the substituent is OH, lower alkyl,lower alkoxy, aryloxy, aryl lower alkoxy, —N(R₁₀)(R₁₁), —COOH,—C(O)—N(R₁₀)(R₁₁), or halo; each of R₈ and R₉, independently, is H, orsubstituted or unsubstituted lower alkyl, cycloalkyl, cycloalkyl loweralkyl, cyloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl,heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent isOH, lower alkyl, lower alkoxy, —N(R₁₀)(R₁₁), —COOH, —C(O)—N(R₁₀)(R₁₁),or halo; and each of R₁₀ and R₁₁, independently, is H, lower alkyl,aryl, aryl lower alkyl, cycloalkyl, cycloalkyl lower alkyl,heterocyclyl, or heterocyclyl lower alkyl; R₁₂ is NR₉, S, or O; R₁₃ issubstituted or unsubstituted lower alkyl wherein the substituent islower alkyl, —OR₁₀,S(O)_(m)R₁₀ (wherein m is 0, 1, or 2) or—N(R₁₀)(R₁₁); and R₁₄ is H or lower alkyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1, wherein each of R₈and R₉, independently, is H; or a pharmaceutically acceptable saltthereof.
 3. A compound of claim 2, wherein R₇ is H; or apharmaceutically acceptable salt thereof.
 4. A compound of claim 3,wherein R₆ is substituted or unsubstituted aryl or cylcoalkyl, and R₅ issubstituted or unsubstituted lower alkyl, cycloalkyl, or cycloalkyllower alkyl; or a pharmaceutically acceptable salt thereof.
 5. Acompound of claim 4, wherein each of R₁, R₂, and R₃, independently, isH; or a pharmaceutically acceptable salt thereof.
 6. A compound of claim2, wherein R₆ is H; or a pharmaceutically acceptable salt thereof.
 7. Acompound of claim 6, wherein R₇ is substituted or unsubstituted aryl orcycloalkyl, and R₅ is substituted or unsubstituted lower alkyl,cycloalkyl, or cycloalkyl lower alkyl; or a pharmaceutically acceptablesalt thereof.
 8. A compound of claim 7, wherein each of R₁, R₂, and R₃,independently, is H; or a pharmaceutically acceptable salt thereof.
 9. Acompound of claim 2, wherein R₅ is substituted or unsubstituted loweralkyl, cycloalkyl, or cycloalkyl lower alkyl, R₆ is halo or substitutedor unsubstituted cycloalkyl or aryl, and R₇ is halo or substituted orunsubstituted cycloalkyl or aryl.
 10. A compound of claim 9, whereineach of R₁, R₂, and R₃, independently, is H; or a pharmaceuticallyacceptable salt thereof.
 11. A compound of claim 1, wherein saidcompound is of the formula:7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine;7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(4-fluorophenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine;7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine;7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(3-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine;7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine;7-(2-amino-1-oxo-3-thio-propyl)-8-(2-hydroxy-methyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine;7-(2-amino-3-thio-propyl)-8-butyl-3-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine;7-(2-amino-1-oxo-3-thio-propyl)-2-(2-methoxyphenyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine;7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-hydroxyphenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(2-methylpropyl)-2-(1-naphthyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(1,1-dimethylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-(phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydroimidazo[1,2a]]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2(2-hydroxy-6-methoxyphenyl)-5,6,7,8-tetrahydro[1,2a]pyrazine;2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydro-7-((thiazolidin-4-yl)carbonyl)-imidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-3-bromo-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2,3-diphenyl-5,6,7,8-tetrahydroimidazo-[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-3-bromo-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-cyclohexyl-8-(cyclohexylmethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-hexyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(2-(4-methoxycyclohexyl)-methyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(4-methoxycyclohexyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(4-methoxycyclohexyl)methyl-2-(2-methoxyphenyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine(cisisomer);7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(4-piperidinylmethyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(2-piperidinylmethyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(3-piperidinylmethyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(1-naphthyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(2-methylthio)-ethyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-amino-1-oxo-3-thiopropyl)-8-(3-indolinylmethyl)-2-(2-methoxyphenyl)-8-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;and7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylimidazol-3-yl)methyl-2-(2-methoxyphenyl)-8-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;or in the form of enantiomers or enantiomeric mixtures; orpharmaceutically acceptable salts thereof.
 12. A compound consisting ofa first compound and a second compound wherein each of said firstcompound and each of said second compound is independently selected fromthe group consisting of a compound of formula (I):

wherein: R₁ is H, lower alkyl, cycloalkylthio, or lower alkylthio, or,together with R₂, form —CH₂— or —C(CH₃)₂—; each of R₂ and R₃,independently, is H or lower alkyl; R₄ is H₂ or O; R₅ is H, orsubstituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, cycloalkenyl loweralkyl, aryl, aryl lower alkyl, heterocyclyl, or heterocyclyl loweralkyl, wherein the substituent is lower alkyl, —O—R₁₀, —S(O)_(m)R₁₀(where m is 0, 1, or 2), —N(R₁₀)(R₁₁), —N—C(O)—R₁₀, —NH—(SO₂)—R₁₀,—CO₂—R₁₀, —C(O)—N(R₁₀)(R₁₁), or —(SO₂)—N(R₁₀)(R₁₁); each of R₆ and R₇,independently, is H, —C(O)NHCHR₁₃CO₂R₁₄, or substituted or unsubstitutedlower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyloalkenyl,cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, orheterocyclyl lower alkyl, wherein the substituent is OH, lower alkyl,lower alkoxy, aryloxy, aryl lower alkoxy, —N(R₁₀)(R₁₁), —COOH,—C(O)—N(R₁₀)(R₁₁), or halo; each of R₈ and R₉, independently, is H, orsubstituted or unsubstituted lower alkyl, cycloalkyl, cycloalkyl loweralkyl, cyloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl,heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent isOH, lower alkyl, lower alkoxy, —N(R₁₀)(R₁₁), —COOH, —C(O)—N(R₁₀)(R₁₁),or halo; and each of R₁₀ and R₁₁, independently, is H, lower alkyl,aryl, aryl lower alkyl, cycloalkyl, cycloalkyl lower alkyl,heterocyclyl, or heterocyclyl lower alkyl; R₁₂ is NR₉, S, or O; R₁₃ issubstituted or unsubstituted lower alkyl wherein the substituent islower alkyl, —OR₁₀, S(O)_(m)R₁₀ (wherein m is 0, 1, or 2) or—N(R₁₀)(R₁₁); and R₁₄ is H or lower alkyl; wherein R₁ in said firstcompound and R₁ in said second compound in combination, form a disulfidebond; or a pharmaceutically acceptable salt thereof.
 13. A compound ofclaim 12, wherein said first and second compounds are identical; or apharmaceutically acceptable salt thereof.
 14. A compound of claim 13,wherein said compound is of the formula:bis-1,1′-[2-amino-3-(7-butyl-2-(2-methoxyphenyl)-4,5,6,7-tetrahydro-imidazo[1,2a]piperazine-6-yl)-3-oxo]propyldisulfide;bis-1,1′-[2-amino-3-(2-(2-methoxyphenyl)-7-(2-methylpropyl)-4,5,6,7-tetrahydro-imidazo[1,2a]piperazine-6-yl)-3-oxo]propyldisulfide;bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)disulfide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydroimidazo[1,2a]-pyrazine]disulfide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(1,1-dimethylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide;bis-1,1′-[2-amino-3-(8-butyl-2-cyclohexyl-5,6,7,8-tetrahydro-imidazo-[1,2a]pyrazin-7-yl)-3-oxo-propyl]disulfide;bis-1,1′-[2-amino-3-(3-bromo-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]-pyrazin-7-yl)-3-oxo-propyl]disulfide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2,3-diphenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-(phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide;bis-1,1′-[2-amino-3-(2-cyclohexyl-8-(cyclohexylmethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazin-7-yl)-3-oxo-propyl]disulfide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-hexyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine]disulfide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide;bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide;orbis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(2-(4-methoxycyclohexyl)-methyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide;or in the form of enantiomers or enantiomeric mixtures orpharmaceutically acceptable salts thereof.
 15. A method of treating aras-dependent tumor or restenosis caused by benign cell proliferation ina subject, which comprises administering to said subject atherapeutically effective amount of the compound or salt of claim
 1. 16.A method of treating a ras-dependent tumor or restenosis caused bybenign cell proliferation in a subject, which comprises administering tosaid subject a therapeutically effective amount of the compound or saltof claim
 12. 17. A method of treating a ras-dependent tumor according toclaim 15 wherein said tumor is located in or on the breast, theprostrate gland, the colon, a lung, an ovary, the epidermis or thepancreas of a mammal.
 18. A method of treating a ras-dependent tumoraccording to claim 16 wherein said tumor is located in or on the breast,the prostrate gland, the colon, a lung, an ovary, the epidermis or thepancreas of a mammal.
 19. A method of treating a ras-dependent tumoraccording to claim 15 wherein said tumor is a hematopoietic tumor foundin a mammal.
 20. A method of treating a ras-dependent tumor according toclaim 16 wherein said tumor is a hematopoietic tumor found in a mammal.